Oleogel-S10 in Dystrophic Epidermolysis Bullosa: A Case Series Evaluating the Impact on Wound Burden Over Two Years.

Epidermolysis bullosa (EB) is a group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Impaired wound healing is central and can lead to serious clinical complications, deformities, and symptoms with a devastating impact on quality of life (QoL). Dressing changes and wound care are central to the management of EB. Recently Oleogel-S10 (also known as birch bark extract or birch triterpenes) was approved in Europe and the UK for treating EB wounds. This approval was based on data from the EASE phase 3 study, which demonstrated Oleogel-S10 accelerated wound healing, reduced total wound burden, and decreased the frequency of dressing changes in patients with EB. A retrospective analysis of medical records was conducted for up to 24 months in 13 patients with EB treated with Oleogel-S10 through an early access programme in Colombia. Effectiveness was assessed by measuring body surface area percentage (BSAP) and total body wound burden (EBDASI). Tolerability and safety were monitored throughout. This is the first report to evaluate the effectiveness of Oleogel-S10 in clinical practice. The results showed a reduction in percentage of BSA affected, from a mean of 27.3% at baseline to 10.4% at 24-month follow-up, despite treatment interruptions. A reduction in EBDASI skin activity score of - 16.2 (24 months) together with a reduced skin damage index score of - 15.4 (18 months) was also observed. Physicians, patients, and caregivers perceived faster wound closure. Adherence with therapy by patients was good, and patients expressed satisfaction with treatment and reported improvements in self-esteem, productivity, and social interaction. Oleogel-S10 was well tolerated; however, two patients reported worsening wounds related to gauze adherence. Two deaths during treatment interruption were reported and was not considered related to Oleogel-S10. This study supports the effectiveness of Oleogel-S10 in a real-world scenario in a country with scarce resources for the treatment of EB.

Use of topical morphine gel in epidermolysis bullosa wounds-A series of case studies.

In recent years, the use of topical morphine gel has increased in the palliative care setting to reduce pain in chronic wounds and fungating tumours. However, there is a paucity of evidence to support its effectiveness. Epidermolysis bullosa (EB) is a rare genetic skin fragility disorder characterised by painful chronic wounds. Adequate control of wound pain can be challenging in this patient group due to other complexities associated with the more severe sub-types of the disease. Topical morphine gel has been used as an adjunct therapy in a small number of EB patients in our tertiary centre in an attempt to improve pain control and quality of life. The purpose of this paper is to demonstrate the efficacy of topical morphine gel used in a variety of EB wounds as well as patient reported reduction in pain through a series of case studies. The case studies suggest a positive effect of topical morphine gel on painful wounds across a spectrum of EB subtypes.

Characterization of wound microbes in epidermolysis bullosa: Results from the epidermolysis bullosa clinical characterization and outcomes database.

BACKGROUND/OBJECTIVES: Patients with epidermolysis bullosa (EB) require care of wounds that are colonized or infected with bacteria. A subset of EB patients are at risk for squamous cell carcinoma, and bacterial-host interactions have been considered in this risk. The EB Clinical Characterization and Outcomes Database serves as a repository of information from EB patients at multiple centers in the United States and Canada. Access to this resource enabled broad-scale analysis of wound cultures. METHODS: A retrospective analysis of 739 wound cultures from 158 patients from 13 centers between 2001 and 2018. RESULTS: Of 152 patients with a positive culture, Staphylococcus aureus (SA) was recovered from 131 patients (86%), Pseudomonas aeruginosa (PA) from 56 (37%), and Streptococcus pyogenes (GAS) from 34 (22%). Sixty-eight percent of patients had cultures positive for methicillin-sensitive SA, and 47%, methicillin-resistant SA (18 patients had cultures that grew both methicillin-susceptible and methicillin-resistant SA at different points in time). Of 15 patients with SA-positive cultures with recorded mupirocin susceptibility testing, 11 had mupirocin-susceptible SA and 6 patients mupirocin-resistant SA (2 patients grew both mupirocin-susceptible and mupirocin-resistant SA). SCC was reported in 23 patients in the entire database, of whom 10 had documented wound cultures positive for SA, PA, and Proteus species in 90%, 50%, and 20% of cases, respectively. CONCLUSIONS: SA and PA were the most commonly isolated bacteria from wounds. Methicillin resistance and mupirocin resistance were reported in 47% and 40% of patients tested, respectively, highlighting the importance of ongoing antimicrobial strategies to limit antibiotic resistance.

Oleogel-S10 Phase 3 study "EASE" for epidermolysis bullosa: study design and rationale.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016-002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. METHODS: EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm2) present for > 21 days and < 9 months, are randomized in a 1:1 ratio to receive wound dressings according to local standard of care with or without Oleogel-S10. Placebo is based on the Oleogel-S10 vehicle, which is sunflower oil formulated to have a consistency indistinguishable from that of the active product. The primary endpoint of the trial, directed by the US health authority according to the required study endpoints for chronic cutaneous ulcer and burn wounds, is to compare the efficacy of Oleogel-S10 versus placebo according to the proportion of patients with complete closure of the target wound within 45 ± 7 days of treatment. Additional EB-focused endpoints include wound burden, patient-reported outcomes, and safety. RESULTS: Results of the primary endpoint are anticipated to be available by H2 2019. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03068780 . EudraCT, 2016-002066-32. Registered on 3 March 2017.

Mechanism of Oleogel-S10: A triterpene preparation for the treatment of epidermolysis bullosa.

Epidermolysis bullosa (EB) is a group of rare heterogeneous, genetic disorders. Currently, there is no effective pharmacological or genetic therapy for all EB subtypes. Dry extract from birch bark and betulin upregulate some pro-inflammatory mediators and downregulate others. The increase in pro-inflammatory cytokines is temporary and attenuated over long-term treatment. This inflammatory stimulus is thought to be prerequisite for a secondary anti-inflammatory response. Dry extract from birch bark and its active marker substances have also been shown to increase the migration of primary human keratinocytes, accelerate wound closure, and promote differentiation of keratinocytes in vitro and in vivo-processes that are essential for reepithelialization and maintenance of the skin barrier. Comprehensive clinical data are available to support the use of Oleogel-S10 in the treatment of partial thickness wounds of different etiologies, and a proof-of-concept Phase 2 study in patients with dystrophic EB has suggested the potential for faster reepithelialization of wounds treated with Oleogel-S10.

Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.

Epidermolysis bullosa is a rare blistering skin disorder that is challenging to manage because skin fragility and repeated wound healing cause itching, pain, limited mobility, and recurrent infections. Cannabidiol, an active cannabinoid found in cannabis, is postulated to have antiinflammatory and analgesic effects. We report 3 cases of self-initiated topical cannabidiol use in patients with epidermolysis bullosa in an observational study. One patient was weaned completely off oral opioid analgesics. All 3 reported faster wound healing, less blistering, and amelioration of pain with cannabidiol use. Although these results demonstrate promise, further randomized, double-blind clinical trials are necessary to provide scientific evidence of our observed benefits of cannabidiol for the treatment of epidermolysis bullosa.

UV-B-induced cutaneous inflammation and prospects for antioxidant treatment in Kindler syndrome.

Kindler syndrome (KS), a rare, autosomal recessive disorder comprises mechanical skin fragility and photosensitivity, which manifest early in life. The progression of the disorder is irreversible and results in tissue damage in form of cutaneous and mucosal atrophy and scarring and epithelial cancers. Here, we unravel molecular mechanisms of increased UV-B sensitivity of keratinocytes derived from KS patients. We show that the pro-inflammatory cytokines, IL-1ß, IL-6 and TNF-α, are upregulated in KS skin and in UV-B irradiated KS keratinocytes. These cytokines are dependent on p38 activation, which is increased in the absence of kindlin-1 and induced by higher ROS levels. Other dysregulated cytokines and growth factors were identified in this study and might be involved in paracrine interactions contributing to KS pathology. We show a direct relationship between kindlin-1 abundance and UV-B induced apoptosis in keratinocytes, whereas kindlin-2 overexpression has no compensatory effect. Importantly, low levels of kindlin-1 are sufficient to relieve or rescue this feature. Reduction of pro-inflammatory cytokines and of UV-B induced apoptosis is a valid therapeutic goal to influence long term complications of KS. Here, we demonstrate that antioxidants and the plant flavonoid luteolin represent feasible topical therapeutic approaches decreasing UV-B induced apoptosis in two-dimensional and organotypic KS cultures. We provide evidence for potential new therapeutic approaches to mitigate the progressive course of KS, for which no cure is available to date. Furthermore, we established organotypic KS models, a valuable in vitro tool for research with a morphology similar to the skin of patients in situ.

Oral viscous budesonide as a first-line approach to esophageal stenosis in epidermolysis bullosa: an open-label trial in six children.

BACKGROUND: Esophageal and pharyngeal problems are common in the majority of patients with epidermolysis bullosa (EB). Repeated blister formation and ulceration, coupled with chronic inflammation, result in scarring and development of esophageal strictures. OBJECTIVE: This study aimed to evaluate whether oral viscous budesonide (OVB) was useful for treating esophageal structures in six pediatric patients (aged 8-17 years) with EB who were affected by dysphagia and esophageal strictures. METHODS: Patients were treated for 4 months with twice-daily oral budesonide nebulizer solution 0.5 mg/2 mL mixed with maltodextrin 5 g and artificial sweeteners. RESULTS: One patient developed a severe oral mycotic infection and discontinued treatment. The other five patients completed the treatment regimen and displayed significantly lower stricture indices (SIs) post-treatment (mean SI ± standard deviation 0.736 ± 0.101 pre-treatment versus 0.558 ± 0.162 post-treatment; p = 0.008). Patients experienced a mean SI decrease of 0.178 (range 0.026-0.296), as well as improved dietary habits in the absence of side effects. CONCLUSION: These findings indicated that topical corticosteroids may significantly alleviate strictures in pediatric patients with EB, thereby limiting the need for endoscopic dilation and considerably improving patients' quality of life.

Improvement of renal function in epidermolysis bullosa patients after gluten free diet: two cases.

Epidermolysis bullosa (EB) is a rare inherited genetic disease characterized by an abnormal response of the skin and mucosa to mechanical trauma. Dystrophic EB (DEB) is very often associated with many extra cutaneous complications. Those complications involve either epithelial associated tissues or other organs. In particular, several renal complications have been described for DEB in the recessive form, such as amyloidosis, post-infection glomerulonephritis, upper and lower urinary tract obstruction and IgA-Nephropathy (IgAN). In the cases reported below we have two patients diagnosed with DEB that showed compromised renal function and proteinuria. The switch of the normal diet toward a gluten free diet resulted beneficial for both patients, since renal function was rescued and proteinuria cured. Moreover, a general health status improvement was recognised, given that nutritional condition was ameliorated and bone growing enhanced. Furthermore, in both patients the presence of autoantibodies anti-COL7 indicating an autoimmune form of the disease. Therefore, patients received low doses of betametasone useful to reduce inflammatory state and to control immune system function. In conclusion, our results prompt us to hypothesized that in these patients, due to the fragility of the intestinal mucosa, the absence in the diet of gluten may be beneficial.

Epidermolysis bullosa nevus-like lesions in a pediatric patient with pyoderma gangrenosum.

Epidermolysis bullosa-associated nevi are recently described dysplastic nevi found in patients with epidermolysis bullosa. These lesions display clinical features of unusual nevi suggestive of malignancy but thus far cases with malignant transformation have not been reported. We describe a case of epidermolysis bullosa-type nevi developing in a child with pyoderma gangrenosum. The nevi in our patient were found in areas previously affected by pyoderma gangrenosum and were clinically concerning for malignancy. However, they were only moderately atypical on light and confocal microscopy. This case demonstrates that pediatric patients with cutaneous inflammation, bullae formation, or both, are at risk for developing unusual nevi at previous sites of skin involvement. Considering the absence of malignant change in these nevi, we suggest that close observation can be employed in cases where this diagnosis can be confirmed both clinically and microscopically.

Colchicine revisited.

Purified from a Mediterranean plant nearly two centuries ago, colchicine has been discovered to inhibit many steps in the inflammatory process. The drug has good oral bioavailability and some enterohepatic recirculation, requiring dose adjustments for kidney disease and avoidance in liver disease. Toxicities are primarily gastrointestinal, hepatic, and hematologic. Colchicine is approved by the U.S. Federal Drug Administration for the treatment and prophylaxis of gout flares but has also been tried with varying success in the treatment of familial Mediterranean fever, primary biliary cirrhosis, psoriasis, Behçet's disease, aphthous stomatitis, linear IgA dermatosis, relapsing polychondritis, Sweet's syndrome, scleroderma, amyloidosis, leukocytoclastic vasculitis, epidermolysis bullosa, and dermatomyositis.

Epidermólisis bullosa: a propósito de un caso / Epidermolysis bullosa: apropos of a case

La epidermólisis bullosa comprende un grupo heterogéneo de enfermedades ampollosas de la piel y las mucosas que son de origen congénito y hereditario. Hacer el diagnóstico no es difícil si se tiene experiencia dermatológica, pero su clasificación es compleja y para ella se necesita considerar la clínica, genética, microscopia y evaluación de laboratorio. El tratamiento de esta enfermedad es también difícil y son necesarias ciertas medidas para proteger al paciente y evitar la aparición de lesiones y las complicaciones derivadas de ellas. Se describe el tratamiento de estas lesiones en un recién nacido, al que se administraron antibióticos profilácticos y se colocaron vendajes en las lesiones. Se describen todos los cuidados y recomendaciones para evitar especialmente los roces y las presiones en estas lesiones y las temperaturas altas.

Epidermolysis bullosa comprises a heterogeneous group of bullous diseases of the skin and the mucosas that are of congenital or hereditary origin. Making the diagnosis is not difficult if one has dermatological experience, but its classification is complex and for it, it is necessary to consider the clinic, genetics, microscopy and lab evaluation. The treatment of this disease is also difficult and certain measures are required to protect the patient and to prevent the appearance of lesions and complications derived from them. It is described the treatment of these lesions in a newborn infant who was administered prophylactic antibiotics, and whose lesions were bandaged. All the care and recommendations to specially avoid the friction and pressures on these lesions and the high temperatures were explained.

[What's new in pediatric dermatology?]. / Quoi de neuf en dermatologie pédiatrique?

The main selected articles in pediatric dermatology covered the following topics: development and maturation of the epidermal barrier in the neonate, iatrogenic events in the neonatal ICU, diagnostic value of minor birthmarks, complications, risk factors and treatment of hemangiomas, coagulopathy in venous malformations, epidemiology and dermoscopy of congenital and acquired melanocytic nevi in childhood, growth of the body surface area, new pathogenic concepts and treatment in atopic dermatitis, the impact of filaggrin deficiency, hereditary factors in Kawasaki disease, severe and drug resistant cases, management of juvenile dermatomyositis, treatment of childhood psoriasis with biologics, the new classification of epidermolysis bullosa and therapeutic approach with cell therapy, neurological impairment in xeroderma pigmentosum, behavioural anomalies in X-linked ichthyosis, guidelines for neurofibromatosis type I, the genetics of an hereditary hypotrichosis, infantile acne, rosacea in childhood, mast cell disease management and, last but not least, treatment of hair lice with silicone.

Effect of prednisolone on secondary messenger metabolism in the lymphocytes from patients with acantholysis bullosa.

Prednisolone in therapeutic concentrations blocks Ca(2+) channels of lymphocyte plasma membranes and prevents arachidonic acid-induced Ca(2+) entry into the cells. Glucocorticoid virtually did not modulate arachidonic acid-stimulated release of Ca(2+) from intracellular stores. No appreciable effect of the hormone on mitogen-induced changes in the intracellular content of cAMP was detected.

Phenytoin in cutaneous medicine: its uses, mechanisms and side effects.

Phenytoin (diphenylhydantoin or Dilantin) is a highly effective and widely prescribed anticonvulsant agent used in the treatment of grand mal and psychomotor epilepsy. In dermatology, phenytoin has been used to treat ulcers, epidermolysis bullosa, and inflammatory conditions. Its mechanism appears to involve its ability to inhibit collagenase. Its topical use for the promotion of wound healing seems promising but requires further trials. The side effects of phenytoin continue to create significant morbidity. Common side effects include gingival hyperplasia, coarsening of the facies, and hirsutism. Rarer cutaneous side effects include drug-induced lupus, purple-hand syndrome, pigmentary alterations, and IgA bullous dermatosis. It can cause generalized cutaneous eruptions that include a maculopapular exanthem, Stevens-Johnson syndrome, generalized exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, and fixed-drug eruptions. Phenytoin is linked to a hypersensitivity syndrome manifested by fever, rash, and lymphadenopathy. Patients receiving phenytoin may develop pseudolymphoma or, rarely, malignant lymphoma and mycosis-fungoides-like lesions. Phenytoin can effect clotting function. Phenytoin can alter vitamin and mineral levels. Prenatal exposure to phenytoin may result in a spectrum of structural, developmental, and behavioral changes known as the fetal hydantoin syndrome. After 60 years of use, phenytoin uses and mechanisms of action have yet to be fully defined; the drug remains a useful tool and an important subject for additional research.